EP3333169A1 - Composés inhibiteurs de jak de pyrazolopyrimidine et procédés - Google Patents

Composés inhibiteurs de jak de pyrazolopyrimidine et procédés Download PDF

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Publication number
EP3333169A1
EP3333169A1 EP17192475.6A EP17192475A EP3333169A1 EP 3333169 A1 EP3333169 A1 EP 3333169A1 EP 17192475 A EP17192475 A EP 17192475A EP 3333169 A1 EP3333169 A1 EP 3333169A1
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alkyl
optionally substituted
pyrazolo
pyrimidine
pyrazol
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EP17192475.6A
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German (de)
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EP3333169B1 (fr
Inventor
Paul Gibbons
Emily Hanan
Wendy Liu
Joseph P. Lyssikatos
Steven R. Magnuson
Rohan Mendonca
Richard Pastor
Thomas E. Rawson
Michael Siu
Mark E. Zak
Aihe Zhou
Bing-Yan Zhu
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Genentech Inc
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Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Pyrazolopyrimidine compounds of Formula I which are inhibitors of one or more Janus kinases, as well as compositions containing these compounds and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells.
  • JAK Janus kinases
  • STAT signal transducer and activator of transcription
  • JAK1, JAK2 and TYK2 exhibit broad patterns of gene expression, while JAK3 expression is limited to leukocytes.
  • Cytokine receptors are typically functional as heterodimers, and as a result, more than one type of JAK kinase is usually associated with cytokine receptor complexes.
  • the specific JAKs associated with different cytokine receptor complexes have been determined in many cases through genetic studies and corroborated by other experimental evidence.
  • JAK1 was initially identified in a screen for novel kinases ( Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607 ). Genetic and biochemical studies have shown that JAK1 is functionally and physically associated with the type I interferon (e.g., IFNalpha), type II interferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes ( Kisseleva et al., 2002, gene 285:1-24 ; Levy et al., 2005, Nat. Rev. Mol. Cell Biol.
  • type I interferon e.g., IFNalpha
  • type II interferon e.g., IFNgamma
  • IL-2 and IL-6 cytokine receptor complexes Kisseleva et al., 2002, gene 285:1-24 ; Levy et al., 2005, Nat. Rev. Mol. Cell Biol.
  • JAK1 knockout mice die perinatally due to defects in LIF receptor signaling ( Kisseleva ct al., 2002, gene 285:1-24 ; O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131 ). Characterization of tissues derived from JAK1 knockout mice demonstrated critical roles for this kinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways.
  • a humanized monoclonal antibody targeting the IL-6 pathway was recently approved by the European Commission for the treatment of moderate-to-severe rheumatoid arthritis ( Scheinecker et al., 2009, Nat. Rev. Drug Discov. 8:273-274 ).
  • JAK2 knockout mice die of anemia ( O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131 ).
  • Kinase activating mutations in JAK2 e.g., JAK2 V617F
  • MPDs myeloproliferative disorders
  • JAK3 associates exclusively with the gamma common cytokine receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for lymphoid cell development and proliferation and mutations in JAK3 result in severe combined immunodeficiency (SCID) ( O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131 ).
  • SCID severe combined immunodeficiency
  • JAK3 and JAK3-mediated pathways have been targeted for immunosuppressive indications (e.g., transplantation rejection and rheumatoid arthritis) ( Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692 ; Changelian et al., 2003, Science 302: 875-878 ).
  • TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes ( Kisseleva ct al., 2002, gene 285:1-24 ; Watford, W.T. & O'Shea, J.J., 2006, Immunity 25:695-697 ). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-I2 and IL-23 signaling.
  • One embodiment includes a compound of Formula I: enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof wherein R 1 , R 2 and R 3 are defined herein.
  • Another embodiment includes a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of one or more Janus kinase activity, selected from JAK1, JAK2, JAK3 and TYK2, in a patient.
  • the method includes administering to the patient a therapeutically effective amount of a compound of Formula I.
  • Another embodiment includes the use of a compound of Formula I for therapy.
  • Another embodiment includes the use of a compound of Formula I for preventing, treating or lessening the severity of a disease.
  • the disease is an autoimmune disease.
  • Another embodiment includes the use of a compound of Formula I in the manufacture of a medicament for preventing, treating or lessening the severity of a disease.
  • the disease is an autoimmune disease.
  • kits for treating a disease or disorder responsive to the inhibition of a Janus kinase includes a first pharmaceutical composition comprising a compound of Formula I and instructions for use.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkyl radical is one to eighteen carbon atoms (C 1 -C 18 ).
  • the alkyl radical is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , or C 1 -C 3 .
  • C 0 alkyl refers to a bond.
  • alkyl groups include methyl (Me,-CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl,-CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl,-CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl,-C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 3 CH 2 CH 3 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 2-
  • Groups of the type (C 0 -C n alkyl)R includes alkyl groups substituted by the R group at any of the atoms in the group available for substitution (in an exemplary embodiment, n is a number from 1-6 and R is -OH, -OCH 3 , -NH 2 , -N(CH 3 ) 2 , -CN, halogen, C 3 -C 6 cycloalkyl, phenyl or 3- to 9-membered heterocyclyl),
  • the group (C 0 -C 3 alkyl)CN includes the groups -CN,-CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , -CH 2 CH 2 CH 2 CN, -CH(CN)CH 2 CH 3 , -CH 2 CH(CN)CH 3 ,-C(CH 3 ) 2 CN, -C(CH 2 CN)CH 3 .
  • the group (C 0 -C 2 alkyl) includes the
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • the alkenyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkenyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkynyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • Examples include, but arc not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein.
  • the cycloalkyl group is 3 to 12 carbon atoms (C 3 -C 12 ).
  • cycloalkyl is C 3 -C 8 , C 3 -C 10 or C 5 -C 10 .
  • the cycloalkyl group, as a monocycle is C 3 -C 8 , C 3 -C 6 or C 5 -C 6 .
  • the cycloalkyl group, as a bicycle is C 7 -C 12 .
  • Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • Aryl refers to a cyclic aromatic hydrocarbon group optionally substituted independently with one or more substituents described herein.
  • the aryl group is 6-20 carbon atoms (C 6 -C 20 ).
  • the aryl group is C 6 -C 9 .
  • the aryl group is a C 6 aryl group.
  • Aryl includes bicyclic groups comprising an aromatic ring with a fused non-aromatic or partially saturated ring.
  • Example aryl groups include, but arc not limited to, phenyl, naphthalenyl, anthracenyl, indenyl, indanyl, 1,2-dihydronapthalenyl and 1,2,3,4-tetrahydronapthyl.
  • aryl includes phenyl.
  • Halogen or halogen refer to F, Cl, Br or I.
  • heterocycle refers to: (i) a saturated or partially unsaturated cyclic group (i.e., having one or more double and/or triple bonds within the ring) (“heterocycloalkyl”), or (ii) an aromatic cyclic group (“heteroaryl”), and in each case, which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being carbon.
  • the heterocyclyl group may be optionally substituted with one or more substituents described below.
  • heterocyclyl includes monocycles or bicycles having 1 to 9 carbon ring members (C 1 -C 9 ) with the remaining ring atoms being heteroatoms selected from N, O, S and P.
  • heterocyclyl includes monocycles or bicycles having C 1 -C 5 , C 3 -C 5 or C 4 -C 5 , with the remaining ring atoms being heteroatoms selected from N. O, S and P.
  • heterocyclyl includes 3-7-membered rings or 3-6 membered rings, containing one or more heteroatoms independently selected from N, O, S and P.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings, containing one or more heteroatoms independently selected from N, O, S and P.
  • heterocyclyl includes bi- or polycyclic or bridged 4-, 5-, 6-, 7-, 8- and 9- membered ring systems, containing one or more heteroatoms independently selected from N. O, S and P.
  • bicycle systems include, but are not limited to, [3,5], [4,5], [5,5], [3,6], [4,6], [5,6], or [6,6] systems.
  • bridged ring systems include, but are not limited to [2.2.1], [2.2.2], [3.2.2] and [4.1.0] arrangements, and having 1 to 3 heteroatoms selected from N, O, S and P.
  • heterocyclyl includes spiro groups having 1 to 4 heteroatoms selected from N, O, S and P.
  • the heterocyclyl group may be a carbon-linked group or heteroatom-linked group.
  • Heterocyclyl includes a heterocyclyl group fused to a cycloalkyl group.
  • heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrapyr
  • heterocyclyl groups herein are optionally substituted independently with one or more substituents described herein.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modem Heterocyclic Chemistry” (W.A. Benjamin. New York, 1968 ), particularly Chapters 1, 3, 4, 6, 7, and 9; " The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present ), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566 .
  • heteroaryl refers to an aromatic carbocyclic radical in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, the heteroaryl group contains 1 to 9 carbon ring atoms (C 1 -C 9 ). In other examples, the heteroaryl group is C 1 -C 5 , C 3 -C 5 or C 4 -C 5 . In one embodiment, exemplary heteroaryl groups include monocyclic aromatic 5-, 6- and 7-membered rings containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • exemplary heteroaryl groups include fused ring systems of up to 9 carbon atoms wherein at least one aromatic ring contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Fused systems can be fused at one or more points on the rings.
  • Heteroaryl includes heteroaryl groups fused with an aryl, cycloalkyl or other heterocyclyl group.
  • heteroaryl groups include, but arc not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothi
  • the heterocyclyl or heteroaryl group is C-attached.
  • carbon bonded heterocyclyls include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • the heterocyclyl or heteroaryl group is N-attached.
  • the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • Treating and “treatment” includes both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer.
  • beneficial or desired clinical results include, but arc not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized ( i . e ., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug thai reaches the general circulation from an administered dosage form.
  • Inflammatory disorder can refer to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function.
  • “Inflammatory disorder” also refers to a pathological state mediated by influx of leukocytes and/or neutrophil chemotaxis.
  • Inflammation refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes and/or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses. Accordingly, inflammatory disorders amenable to treatment with Formula I compounds encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system.
  • Specific defense system refers to the component of the immune system that reacts to the presence of specific antigens.
  • inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity response mediated by T-cells.
  • Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e.g., kidney and bone marrow transplants, and graft versus host disease (GVHD), are further examples or inflammatory reactions of the specific defense system.
  • nonspecific defense system refers to inflammatory disorders that arc mediated by leukocytes that are incapable of immunological memory (e.g., granulocytes, and macrophages).
  • inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ARDS) or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis; dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.
  • ARDS adult (acute) respiratory distress syndrome
  • multiple organ injury syndromes reperfusion injury
  • acute glomerulonephritis reactive arthritis
  • dermatoses with acute inflammatory components acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes;
  • Autoimmune disease refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
  • Allergic disease refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy.
  • Arthritic disease refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies.
  • Dermatis refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of etiologies.
  • Transplant rejection refers to any immune reaction directed against grafted tissue, such as organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia.
  • the therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation.
  • “Inflammatory cell activation” refers to the induction by a stimulus (including, but not limited to, cytokines, antigens or auto-antibodies) of a proliferative cellular response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatability antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells). It will be appreciated by persons skilled in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation
  • NSAID is an acronym for "non-steroidal anti-inflammatory drug” and is a therapeutic agent with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation).
  • non-steroidal is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action.
  • analgesics NSAIDs are unusual in that they arc non-narcotic. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.
  • NSAIDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes.
  • COX-1 cyclooxygenase-1
  • COX-2 cyclooxygenase-2
  • Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2).
  • Prostaglandins act (among other things) as messenger molecules in the process of inflammation.
  • COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • squamous cell cancer e.g., epithelial squamous cell cancer
  • lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • NSCLC non-small cell lung cancer
  • adenocarcinoma of the lung and squamous carcinoma of the lung cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer
  • chemotherapeutic agent is a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech, Inc./OSI Pharm.), Trastuzumab (HERCEPTIN®, Genentech, Inc.); bevacizumab (AVASTIN®, Genentech, Inc.); Rituximab (RITUXAN®, Genentech, Inc./Biogen Idec, Inc.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Lectrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliptalin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
  • ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (doxetaxel; Rhône-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; cap
  • chemotherapeutic agent include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole),
  • SERMs
  • Humanized monoclonal antibodies with therapeutic potential as agents in combination with the Janus kinase inhibitors of the invention include: adalimumab, etanercept, infliximab, alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab,
  • prodrug refers to a precursor or derivative form of a pharmaceutically active substance that is less efficacious to the patient or cytotoxic to tumor cells compared to the parent drug and is capable of being enzymatically or hydrolytically activated or converted into the more active parent form. See, e.g ., Wilman, "Prodrugs in Cancer Chemotherapy” Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Harbor (1986 ) and Stella et al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985 ).
  • the prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs which can be converted into the more active cytotoxic free drug.
  • cytotoxic drugs that can be derivatized into a prodrug form for use in this invention include, but are not limited to, those chemotherapeutic agents described above.
  • Liposome refers to a vesicle composed of one or more lipids, phospholipids and/or surfactants, which is useful for delivery of a drug (such as a compound of Formula I and, optionally, a chemotherapeutic agent) to a mammal.
  • a drug such as a compound of Formula I and, optionally, a chemotherapeutic agent
  • the components of the liposome can be in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage. administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which arc non-superimposable mirror images of one another.
  • d and 1 or (+) and (-) arc employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • phrases "pharmaceutically acceptable salt,” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula I.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p -toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of Formula I.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex when: the solvent molecule is water.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protccting groups include acetyl, trifluoroacetyl, phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, and tetrahydropyranyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protccting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl.
  • patient includes human patients and animal patients.
  • animal includes companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • JAK kinase and “Janus kinase” refer to the JAK1, JAK2. JAK3 and TYK2 protein kinases.
  • compound of this invention and “compounds of the present invention”, and “compounds of Formula I”, unless otherwise indicated, include compounds of Formula I, formulas 1a-1n and stereoisomers, tautomers, solvates, metabolites, salts (e.g., pharmaceutically acceptable salts) and prodrugs thereof.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds of Formula I and formulas 1a-1n. wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • a compound of Formula I. and pharmaceutical formulations thereof, arc provided that are useful in the treatment of diseases, conditions and/or disorders responsive to the inhibition of one or more Janus kinases.
  • Another embodiment includes compounds of Formula I: enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein:
  • Another embodiment includes compounds of Formula I: enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein:
  • R 2 is selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroly, pyridazinyl, triazinyl, oxadiazolyl, triazolyl, thiadiazolyl or furazanyl, and wherein R 2 is optionally substituted with 1-3 R 4 . In one embodiment, R 2 is selected from pyridinyl or pyrazolyl, optionally substituted with 1-3 R 4 .
  • R 2 is selected from thiazolyl, pyridinyl or pyrazolyl, optionally substituted with 1-3 R 4 .
  • R 4 is independently C 1 -C 6 alkyl, -(C 0 -C 6 alkyl)OR 6 , -(C 0 -C 6 alkyly)SR 6 ,-(C 0 -C 6 alkyl)NR 6 R 7 , -(C 0 -C 6 alkyl)CF 3 , -(C 0 -C 6 alkyl)C(O)R 6 , -(C 0 -C 6 alkyl)C(O)OR 6 , -(C 0 -C 6 alkyl)C(O)NR 6 R 7 , -(C 0 -C 6 alkyl)(C 3 -C 6 cycloalkyl) or -(C 0 -C 6 alkyl)(3-6-membered heterocyclyl), wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, oxo, halogen,-CF 3 , -OR 8 or
  • R 4 is C 1 -C 6 alkyl, halogen, -(C 0 -C 6 alkyl)CN, -(C 0 -C 6 alkyl)OR 6 , -(C 0 -C 6 alkyl)NR 6 R 7 , -(C 0 -C 6 alkyl)CF 3 , -(C 0 -C 6 alkyl)C(O)R 6 , -(C 0 -C 6 alkyl)C(O)OR 6 , -(C 0 -C 6 alkyl)C(O)NR 6 R 7 , -(C 0 -C 6 akyl)NR 6 C(O)R 7 , -(C 0 -C 6 alkyl)C(O)3-6 membered heterocyclyl,-(C 0 -C 6 alkyl)(C 3 -C 6 cycloalkyl), -(C 0 -C 6 alkyl)
  • R 3 is phenyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyL thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, triazolyl, thiadiazolyl or furazanyl, and wherein R 3 is optionally substituted by 1-5 R 5 . In one embodiment, R 3 is phenyl, optionally substituted by 1-3 R 5 .
  • R 3 is phenyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, triazolyl, thiadiazolyl, cyclohexenyl, dihydrobenzofuranyl, piperidinyl, pyridinonyl, pyrrolidinyl or furazanyl, and wherein R 3 is optionally substituted by 1-5 R 5 .
  • R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -(C 0 -C 3 alkyl)OR 11 ,-(C 0 -C 3 alkyl)SR 11 , -(C 0 -C 3 alkyl)NR 11 R 12 , -(C 0 -C 3 alkyl)OCF 3 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -CF 3 , -(C 0 -C 4 alkyl)OR 13 or-(C 0 -C 3 alkyl)NR 13 R 14 .
  • R 3 is phenyl, optionally substituted by 1-3 R 5 ; and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -(C 0 -C 3 alkyl)OR 11 , -(C 0 -C 3 alkyl)SR 11 , -(C 0 -C 3 alkyl)NR 11 R 12 .
  • alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -CF 3 , -(C 0 -C 3 alkyl)OR 13 or -(C 0 -C 3 alkyl)NR 13 R 14 .
  • R 3 is phenyl, pyridinyl, dihydrobenzofuranyl, piperidinyl, pyrrolidinyl, pyridinonyl, imidazolyl or isoxazolyl, wherein R 3 is optionally substituted by 1-3 R 5 ; and R 5 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, halogen, -CN,-O(C 1 -C 6 alkyl), -S(C 1 -C 6 alkyl), -O(C 3 -C 6 cycloalkyl), -S(C 3 -C 6 cycloalkyl), -(C 0 -C 3 alkyl)NR 11 R 12 , -OCF 3 , -OCHF 2 , or -CF 3 , wherein said alkyl, alken
  • R 1 is hydrogen, OR 8 or -NR 6 R 7 . In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is -NH 2 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)OR 6 or -(C 0 -C 6 alkyl)SR 6 , and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)OR 6 or -(C 0 -C 3 alkyl)SR 6 , and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 , R 3 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)CF 3 , and wherein R 4 is independently optionally substituted by C 1 -C 4 alkyl, -OR 8 or-NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)CF 3 , and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or-NR 8 R 9 , R 1 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)NR 6 R 7 or -(C 0 -C 6 alkyl)(3-6-membered heterocyclyl), and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)NR 6 R 7 or -(C 0 -C 6 alkyl)(3-6-membered heterocyclyl), and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or-NR 8 R 9 , R 3 is phenyl, optionally substituted by 1-3 R 4 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)(C 1 -C 6 cycloalkyl), and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl,-OR 8 or -NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)(C 3 -C 6 cycloalkyl), and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 , R 3 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)C(O)OR 6 or -(C 0 -C 6 alkyl)C(O)NR 6 NR 7 , and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)C(O)OR 6 , and wherein R 4 is independently optionally substituted by C 1 -C 3 alkyl.
  • R 3 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen. -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is C 0 -C 6 alkyl, and wherein R 4 is independently optionally substituted by halogen, -OR 8 or -NR 8 R 4 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is C 0 -C 6 alkyl, and wherein R 4 is independently optionally substituted by halogen, -OR 8 or -NR 8 R 9 , R 3 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 . -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -(C 0 -C 6 alkyl)CN, and wherein R 4 is independently optionally substituted by halogen, -OR 8 or -NR 8 R 9 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is -C 0 -C 6 alkyl)CN, and wherein R 4 is independently optionally substituted by halogen, -OR 8 or -NR 8 R 9
  • R 3 is phenyl, optionally substituted by 1-3 R 5 , and R 5 is independently C 1 -C 6 alkyl, halogen, -CN.
  • -OR 11 ,-SR 11 or -CF 3 wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is C 1 -C 6 alkyl optionally substituted by oxo, -OR 8 , -NR 8 R 9 , -CN.
  • -OR 8 , -NR 8 R 9 ,-CN, halogen or C 1 -C 3 alkyl, and R 3 is phenyl optionally substituted by 1-3 R 5 .
  • R 2 is pyrazolyl, optionally substituted by R 4 , wherein R 4 is-CH 2 C(OH)C 1 -C 3 alkyl optionally substituted by halogen), -CH 2 C(O)NR 6 NR 7 or -CH 2 C(O)(4-6 membered heterocyclyl), wherein R 4 is optionally substituted by oxo, -OR 8 , -NR 8 R 9 , -CN. halogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and R 3 is phenyl optionally substituted by 1-3 R 5 ,
  • R 2 is pyridinyl, optionally substituted by C 1 -C 6 alkyl and said alkyl is optionally substituted by halogen.
  • R 2 is pyridinyl, optionally substituted by C 1 -C 6 alkyl and said alkyl is optionally substituted by halogen
  • R 3 is phenyl, optionally substituted by 1-3 R 5
  • R 5 is independently C 1 -C 6 alkyl, halogen, -CN, -OR 11 , -SR 11 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, -CF 3 , -OR 13 or -NR 13 R 14 .
  • R 4 is -(C 0 -C 6 alkyl)OR 6 or -(C 0 -C 6 alkyl)SR 6 , wherein said alkyl is independently optionally substituted by halogen. C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 . In one embodiment, R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)CF 3 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)NR 6 R 7 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo. -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)(3-6-mcmbered heterocyclyl), wherein said alkyl and heterocyclyl arc independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or-NR 8 R 9 .
  • said 3-6-membered heterocyclyl is oxetanyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, oxazolyl, isoxazolyl and tetrahydropyranyl, optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)C(O)(3-6-membered heterocyclyl), wherein said alkyl and heterocyclyl are independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo,-OR 8 or -NR 8 R 9 .
  • said 3-6-membered heterocyclyl is oxetanyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, dihydropyrrolyl and tetrahydropyranyl, optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)(C 3 -C 6 cycloalkyl), wherein said alkyl and cycloalkyl are independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is -(C 0 -C 6 alkyl)(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is cyclopentyl or cyclohexyl optionally substituted by C 1 -C 3 alkyl, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)C(O)OR 6 , -(C 0 -C 6 alkyl)C(O)NR 6 NR 7 , -(C 0 -C 6 alkyl)OC(O)NR 6 , -(C 0 -C 6 alkyl)NR 6 C(O)OR 7 , -(C 0 -C 6 alkyl)NR 6 C(O)NR 7 or -(C 0 -C 6 alkyl)NR 6 C(O)R 7 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl optionally substituted by halogen, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 4 is -(C 0 -C 6 alkyl)CN, wherein said alkyl is optionally substituted by halogen, oxo, -OR 8 or -NR 8 R 9 .
  • R 4 is -CH 2 CN, -CH 2 CH 2 CN or-CH(CH 3 )CN.
  • R 4 is halogen. In one embodiment, R 4 is F. Cl. Br or I. In one embodiment, R 4 is F or Cl.
  • R 3 is: wherein n is 0, 1, 2 or 3 and the wavy line represents the point of attachment to R 2 . In one embodiment, n is 2. In one embodiment, R 3 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 3 is phenyl or pyridinyl, optionally substituted by C 1 -C 6 alkyl, halogen, -CN, -(C 0 -C 3 alkyl)OR 6 , -(C 0 -C 3 alkyl)SR 6 , -(C 0 -C 3 alkyl)NR 6 R 7 , -(C 0 -C 3 alkyl)OCF 3 or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, -CF 3 ,-(C 0 -C 3 alkyl)OR 8 or -(C 0 -C 3 alkyl)NR 8 R 9 .
  • R 3 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 3 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 3 is 4-6 membered hererocyclyl optionally substituted by C 1 -C 6 alkyl, halogen. -CN. -(C 0 -C 3 alkyl)OR 6 , -(C 0 -C 1 alkyl)SR 6 , -(C 0 -C 3 alkyl)NR 6 R 7 , -(C 0 -C 3 alkyl)OCF, or -CF 3 , wherein said alkyl is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo,-CF 3 , -(C 0 -C 3 alkyl)OR 8 or -(C 0 -C 3 alkyl)NR 8 R 9 .
  • said heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, and pyridinonyl.
  • R 3 is selected from: wherein the wavy line represents the point of attachment to R 2 .
  • R 2 is selected from: wherein R 10 is independently selected from hydrogen or R 4 , and the wavy line represents the point of attachment to Formula 1.
  • R 2 is selected from: wherein R 10 is independently selected from hydrogen or R 4 , and the wavy line represents the point of attachment to Formula I.
  • R 2 is selected from: wherein R 10 is independently selected from hydrogen or R 4 , and the wavy line represents the point of attachment to Formula I.
  • R 2 is selected from: or pyridinyl
  • R 10 is hydrogen or R 4
  • the wavy line represents the point of attachment to Formula I and R 2 , respectively.
  • -R 2 -R 3 in Formula I is wherein , R 10 is hydrogen or R 4 , and the wavy line represents the point of attachment to Formula I.
  • -R 2 -R 3 in Formula I is wherein n is 0, 1, 2 or 3, R 10 is hydrogen or R 4 , and the wavy line represents the point of attachment of R 2 to Formula I.
  • Another embodiment includes a compound of Formula I that has K i and/or EC 50 that is at least 15 fold, alternatively 10 fold, or 5 fold or more selective in inhibiting one Janus kinase activity over inhibiting one or more of the other Janus kinase activities.
  • the compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I, including but not limited to: diastereomers, enantiomers, and atropisomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers arc contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and it is intended thai the invention, as defined by the claims, embrace both solvated and unsolvated forms.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which arc interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the present invention also embraces isotopically-labeled compounds of Formula I, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or clement as specified are contemplated within the scope of the invention.
  • Exemplary isotopes that can be incorporated into compounds of Formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 14 N, 15 O, 17 O, 18 O, 12 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Certain isotopically-labeled compounds of Formula I e.g., those labeled with 3 H and 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes arc useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.. 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Compounds of Formula I may be synthesized by synthetic routes described herein. In certain embodiments, processes well-known in the chemical arts can be used, in addition to, or in light of, the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed .),
  • Compounds of Formula I may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds of Formula I.
  • Libraries of compounds of Formula I may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof
  • reaction Schemes 1-13 depicted below provide routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
  • specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Suitable amino-protocting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • NH-Pg amino-protocting groups
  • BOC t-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9-fluorenylmethyleneoxycarbonyl
  • Compounds of Formula I can be synthesized as shown in Reaction Scheme 1.
  • commercially available benzoic acids can be reacted with potassium 3-ethoxy-3-oxopropanoate in the presence of carbonyldiimidazole (CDI) and magnesium chloride to give ⁇ -keto-ester 2.
  • Compound 2 can be heated with 1,1-dimethoxy-N,N-dimethylmethanamine (DMFDMA) to give compound 3.
  • Cyclization of compound 3 with hydrazine in ethanol provides pyrazole compound 4.
  • Methylation of compound 4 with iodomethane in the presence of a base such as cesium carbonate affords a mixture of the regioisomers 5a and 5b.
  • Reaction Scheme 3 illustrates the synthesis of compounds of Formula 1d
  • Subjection of commercially available anilines to diazotization and tin chloride mediated reduction provides compound 11.
  • Condensation of compound 11 with 3-iminocrotonitrile in ethanolic hydrochloric acid generates amino-pyrazole compound 12.
  • Coupling of compound 12 with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of PyAOP, DIEA. and DMAP provides compounds of Formula 1d.
  • Reaction Scheme 4 illustrates the synthesis of compounds of Formula 1e.
  • 5-Bromo-2-methylpyridine can be oxidized with m -chloroperoxybenzoic acid to give compound 13.
  • Nitration of compound 13 to give compound 14, followed by tin chloride reduction yields aminopyridine 15.
  • Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid can be converted to the corresponding acid chloride with oxalyl chloride, and then reacted with compound 15 or other commercially available amino pyridines to form compound 16.
  • These compounds may be subjected to Suzuki cross-coupling conditions with aryl boronic acids to provide compounds of Formula 1e.
  • Reaction Scheme 6 illustrates a method for the synthesis of compounds of Formula 1g and 1f.
  • Compound 18 may be cyclized with hydrazine to yield compound 10, which may then be coupled with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid under amide formation conditions using HATU to provide compounds of Formula 1c.
  • Alkylation of compound 1c with alkyl halides in the presence of cesium carbonate gives compounds of Formula 1f.
  • Reaction of compound 1c with 2,2-dimethyloxirane in the presence of cesium carbonate provides compounds of Formula 1g.
  • Reaction Scheme 7 illustrates the synthesis of compounds of Formula 1h.
  • Amide formation using HATU with 4-bromo-1-methyl-1H-pyrazol-3-amine and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid provides compound 19.
  • Palladium catalyzed Suzuki coupling of compound 19 with various boronic acids provides compounds of Formula 1h.
  • Reaction Scheme 8 illustrates the synthesis of compounds of Formula 1i.
  • a solution of the appropriately substituted phenylhydrazine can be heated under reflux with excess acrylonitrile in a solvent such as ethanol to give compounds of formula 21.
  • Hydrazines 21 can be oxidized using iron(III) sulfate in dilute sulfuric acid to give compounds of formula 22.
  • Compounds 22 can be cyclized in dilute sodium hydroxide solution to give compounds of formula 23.
  • Reaction of 22 with previously prepared pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride gives the final compounds of formula 1i.
  • Reaction Scheme 10 illustrates the synthesis of compounds of Formula 1j and 1k.
  • Pyrazole compounds 1c (prepared as described in either Reaction Scheme 2 or Reaction Scheme 9) may be alkylated with substituted epoxides in the presence of cesium carbonate to give the regioisomeric compounds of Formula 1j and 1k.
  • Compounds of Formula 1m can be synthesized as shown in Reaction Scheme 11.
  • Commercially available acetophenones can be acylated with potassium tert -butoxide and ethyl acetate to generate di-ketone compounds of formula 28.
  • Compounds 28 can be treated with sodium nitrite in the presence of acetic acid and water to provide hydroxyimino compounds 29, which may be subsequently cyclized with hydrazine to yield amino-pynizole compounds 30.
  • Amide bond coupling with commercially available pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of PyAOP, DIEA, and DMAP provides compounds of Formula 1m.
  • Reaction Scheme 12 An alternate method for the synthesis of compounds of Formula 1a and 1b is shown in Reaction Scheme 12.
  • Commercially available 4-Nitro-1H-pyrazole can be reacted with alkyl bromides in the presence of cesium carbonate at 55°C for 12 hours to give compound 31.
  • Compound 31 can be reacted with aryl bromides in N,N-Dimethylacetamide in the presence of Palladium (II) acetate, Di(1-adamntyl)-n-butylphosphine, potassium carbonate and trimethylacetic acid to give compounds 32a and 32b.
  • the ratio of products 32a:32b varies depending on the substituent R1, but the reaction generally favors formation of product 32b.
  • Compounds 32a and 32b can be reduced to compounds 33a and 33b in the presence of iron and ammonium chloride in ethanol and water. Coupling of compounds 33a and 33b with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of PyAOP, DIEA, and DMAP can provide compounds of Formula 1a and 1b.
  • Reaction Scheme 16 illustrates the synthesis of compounds of formula 1R.
  • Nitro-SEM pyrazole compound 24, prepared as in Reaction Scheme 9, may be regioselectively deprotonated with lithium hexamethyldisilazide at low temperature and quenched with hexachloroethane to yield 40.
  • the nitro group of intermediate 41 can be reduced in the presence of iron and ammonium chloride to generate amino pyrazoles 42.
  • Reaction Scheme 17 illustrates an alternate synthesis for compounds of formula 10.
  • Nitro-SEM pyrazole compound 24, prepared as in Reaction Scheme 9, may be regioselectively deprotonated with lithium hexamethyldisilazide at low temperature and quenched with iodine to yield 43.
  • the nitro group of compound 43 can be reduced in the presence of iron and ammonium chloride, followed by Boc protection to generate compound 44.
  • Compound 44 may be coupled under Suzuki conditions with aryl boronic acids or aryl boronates to yield compounds 45. After cleavage of the Boc group with tin tetrachloride, compounds of formula 10 are obtained.
  • Compounds of Formula 1u can be synthesized as shown in Reaction Scheme 20.
  • commercially available substituted benzaldehydes can be converted to compounds 49 by treatment with a cyanide source such as sodium cyanide in the presence of ammonium chloride and ammonium hydroxide.
  • Compounds 49 can be coupled to carboxylic acids to provide compounds 50 using an amide coupling reagent such as HATU and base such as diisopropylethylamine.
  • Compounds 50 can be treated with hydrogen peroxide and potassium carbonate to provide compounds 51. Cyclization of diamido compounds 51 using Lawesson's reagent and pyridine provides amino thiazolo compounds 52.
  • Compounds of formula 1u can prepared by treatment of compounds 52 with previously prepared pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride in pyridine.
  • compounds of Formula 1u can be synthesized as shown in Reaction Scheme 21.
  • compounds 53 can be prepared by treatment of commercially available substituted acetophenones with diethyl carbonate and subsequent bromination using for example bromine in dioxane.
  • Treatment of compounds 53 with a suitably substituted thioamide or thiourea provides thiazole compounds 54.
  • Compounds 54 can be hydrolysed using an aqueous base such as potassium hydroxide in a compatible solvent such as THF to afford acid compounds 55.
  • Compounds 56 can be prepared by treatment of compounds 55 with diphenylphosphoryl azide (DPPA) in tert-butanol. Deprotection of compounds 56 under acidic conditions provides amino compounds 52.
  • Compounds of formula 1u can prepared by treatment of compounds 52 with previously prepared pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride in pyridine.
  • primary amine or secondary amine groups may be converted into amide groups (-NHCOR' or -NRCOR') by acylation.
  • Acylation may be achieved by reaction with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable coupling agent such HATU (O-(7-azabenzotriazol-1-yl)-N,N.N',N'-tetramethyluronium hexufluorophosphale) in a suitable solvent such as dichloromethane.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N.N',N'-tetramethyluronium hexufluorophosphale
  • amine groups may be converted into sulphonamide groups (-NHSO 2 R' or -NR"SO 2 R') groups by reaction with an appropriate sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.
  • Primary or secondary amine groups can be converted into urea groups (-NHCONR'R" or -NRCONR'R”) by reaction with an appropriate isocyanate in the presence of a suitable base such as triethylamine, in a suitable solvent, such as dichloromethane.
  • An amine (-NH 2 ) may be obtained by reduction of a nitro (-NO 2 ) group, for example by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • the transformation may be carried out by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at an appropriate temperature, for example from about -78°C to the reflux temperature of the solvent.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aldehyde groups may be converted to amine groups (-CH 2 NR'R")) by reductive amination employing an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a borohydride for example sodium triacetoxyborohydride or sodium cyanoborohydride
  • a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol
  • Aldehyde groups may be obtained by reduction of ester groups (such as -CO 2 Et) or nitriles (-CN) using diisobutylaluminium hydride in a suitable solvent such as toluene.
  • ester groups such as -CO 2 Et
  • -CN nitriles
  • aldehyde groups may be obtained by the oxidation of alcohol groups using any suitable oxidising agent known to those skilled in the art.
  • Ester groups (-CO 2 R') may be converted into the corresponding acid group (-CO 2 H) by acid- or base-catalused hydrolysis, depending on the nature of R. If R is t -butyl, acid-catalysed hydrolysis can be achieved for example by treatment with an organic acid such as trifluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid such as hydrochloric acid in an aqueous solvent.
  • Carboxylic acid groups may be converted into amides (CONHR' or -CONR'R") by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU
  • carboxylic acids may be homologated by one carbon (i.e -CO 2 H to-CH 2 CO 2 H) by conversion to the corresponding acid chloride (-COCl) followed by Arndt-Eistert synthesis.
  • -OH groups may be generated from the corresponding ester (e.g. -CO 2 R'), or aldehyde (-CHO) by reduction, using for example a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid (-CO 2 H), using for example lithium aluminium hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p- toluenesulfonyloxy group using conditions known to those skilled in the art.
  • halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p- toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thioyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.
  • a base e.g. triethylamine
  • alcohol, phenol or amide groups may be alkylated by coupling a phenol or amide with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • alkylation may be achieved by deprotonation using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkyl halide.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as n -butyt or t -butyl lithium, optionally at a low temperature, e.g. around -78 °C, in a solvent such as tetrahydrofuran, and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n -butyt or t -butyl lithium
  • a solvent such as tetrahydrofuran
  • an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using N , N -dimethylformamide as the electrophile.
  • Aromatic halogen substituents may alternatively be subjected to metal (e.g.
  • Aromatic halogen substituents may also undergo nucleophilic displacement following reaction with an appropriate nucleophile such as an amine or an alcohol.
  • an appropriate nucleophile such as an amine or an alcohol.
  • such a reaction may be carried out at elevated temperature in the presence of microwave irradiation.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and arc considered as part of this invention.
  • a single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents ( Eliel, E. and Wilen. S., Stereochemistry of Organic Compounds. John Wiley & Sons, Inc., New York, 1994 ; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975 )).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • suitable method including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair ( Eliel, E. and Wilcn, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322 ).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ( Chiral Liquid Chromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989 ): Okamoto, J. of Chromatogr. 513:375-378 (1990 )).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • Positional isomers for example E and Z forms, of compounds of Formula I, and intermediates for their synthesis, may be observed by characterization methods such as NMR and analytical HPLC.
  • the E and Z isomers may be separated, for example by preparatory HPLC.
  • JAK3 or TYK2 kinase domains JAK1 amino acid residues N852-D1154 according to the numbering of GenBank sequence accession number P23458, JAK2 amino acid residues D812-G1132 according to the numbering of GenBank sequence accession number MP_004963.1; JAK3 amino acid residues S783-S1124 according to the numbering of GenBank sequence accession number P52333, and TYK2 amino acid residues N873-C1187 according to the numbering of GenBank sequence accession number P29597).
  • the activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains can be measured by a number of direct and indirect methods, including quantification of pbosphorylation of peptide substrates derived from the human JAK3 protein ( Saltzman et al., Biochem. Biophys. Res. Commun. 246:627-633 (2004 )).
  • the activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains was measured in vitro by monitoring phosphorylation of JAK3 derived peptides using the Caliper LabChip technology (see Examples).
  • the compounds of the present invention arc tested for their capacity to inhibit a Janus kinase activity and activation (primary assays) and for their biological effects on growing cells (secondary assays) as described herein.
  • Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.
  • the method includes the step of administering to a patient a therapeutically effective amount of a compound of Formula I.
  • the disease is an autoimmune disease.
  • Another embodiment includes the use of a compound of Formula I for therapy.
  • Another embodiment includes the use of a compound of Formula I for preventing, treating or lessening the severity of a disease.
  • the disease is an autoimmune disease.
  • Another embodiment includes the use of a compound of Formula I in the manufacture of a medicament for preventing, treating or lessening the severity of a disease.
  • the disease is an autoimmune disease.
  • a compound of Formula I is administered to a patient in a therapeutically effective amount to treat or lessen the severity of a disease or condition responsive to the inhibition of a Janus kinase activity, and said compound is at least 15 fold, alternatively 10 fold, alternatively 5 fold or more selective in inhibiting one Janus kinase activity over inhibiting one or more of the other Janus kinase activities.
  • the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induccd platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.
  • the disease or condition is cancer.
  • the disease is a myeloproliferative disorder.
  • the myeloproliferative disorder is polycythemia vera, essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • the cancer is breast, ovary, cervix, prostate, testis, penile, genitourinary tract, seminoma, esophagus, larynx, gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicular carcinoma, melanoma, lung, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of the lung, colon, pancreas, thyroid, papillary, bladder, liver, biliary passage, kidney, bone, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivary gland, pharynx, small intestine, colon, rectum, anal, renal, prostate, vulval, thyroid, large intestine, endometrial, uterine, brain, central nervous system, cancer of the peritoneum, hepatocellular cancer, head cancer, neck cancer,
  • the cardiovascular disease is restenosis, cardiomegaly, atherosclerosis, myocardial infarction or congestive heart failure.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.
  • the inflammatory disease is inflammatory bowel disease, rheumatoid arthritis, psoriasis, contact dermatitis or delayed hypersensitivity reactions.
  • the autoimmune disease is lupus or multiple sclerosis.
  • the autoimmune disease is Crohn's disease, ulcerative colitis, Collagenous colitis, Lymphocytic colitis. Ischaemic colitis, Diversion colitis. Behçet's syndrome, Infective colitis and Indeterminate colitis.
  • Evaluation of drug-induced immunosuppression by the compounds of the invention may be performed using in vivo functional tests, such as rodent models of induced arthritis and therapeutic or prophylactic treatment to assess disease score, T cell-dependent antibody response (TDAR), and delayed-type hypersensitivity (DTH).
  • Other in vivo systems including murine models of host defense against infections or tumor resistance ( Burleson GR, Dean JH, and Munson AE. Methods in Immunotoxicology, Vol. 1. Wiley-Liss, New York, 1995 ) may be considered to elucidate the nature or mechanisms of observed immunosuppression.
  • the in vivo test systems can be complemented by well-established in vitro or ex vivo functional assays for the assessment of immune competence.
  • These assays may comprise B or T cell proliferation in response to mitogens or specific antigens, measurement of signaling through one or more of the Janus kinase pathways in B or T cells or immortalized B or T cell lines, measurement of cell surface markets in response to B or T cell signaling, natural killer (NK) cell activity, mast cell activity, mast cell degranulation, macrophage phagocytosis or kill activity, and neutrophil oxidative burst and/or chemotaxis.
  • NK natural killer
  • NK natural killer
  • mast cell activity mast cell activity
  • mast cell degranulation macrophage phagocytosis or kill activity
  • neutrophil oxidative burst and/or chemotaxis neutrophil oxidative burst and/or chemotaxis.
  • the in vitro and ex vivo assays can be applied in both preclinical and clinical testing using lymphoid tissues and/or peripheral blood ( House RV. "Theory and practice of cytokine assessment in immunotoxicology” (1999) Methods 19:17-27 ; Hubbard AK. "Effects of xenobiotics on macrophage function: evaluation in vitro” (1999) Methods; 19:8-16 ; Lebrec H, et al (2001) Toxicology 158:25-29 ).
  • Collagen-Induced Arthritis 6-week detailed study using an autoimmune mechanism to mimic human arthritis; rat and mouse models (Example 68).
  • Collagen-induced arthritis is one of the most commonly used animal models of human rheumatoid arthritis (RA). Joint inflammation, which develops in animals with CIA, strongly resembles inflammation observed in patients with RA. Blocking tumor necrosis factor (TNF) is an efficacious treatment of CIA, just as it is a highly efficacious therapy in treatment of RA patients.
  • CIA is mediated by both T-cells and antibodies (B-celts). Macrophages arc believed to play an important role in mediating tissue damage during disease development.
  • CIA is induced by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CPA). It is most commonly induced in the DBA/1 mouse strain, but the disease can also be induced in Lewis rats.
  • CPA Complete Freund's Adjuvant
  • CD69 is the early activation marker in leukocytes including T cells, thymocytes, B cells, NK cells, neutrophils, and eosinophils.
  • the CD69 human whole blood assay determines the ability of compounds to inhibit the production of CD69 by B lymphocytes in human whole blood activated by crosslinking surface IgM with goat F(ab')2 antihuman IgM.
  • the T-cell Dependent Antibody Response is a predictive assay for immune function testing when potential immunotoxic effects of compounds need to be studied.
  • TDAR has proven to be a highly predictable assay for adult exposure immunotoxicity detection in mice based on the US National Toxicology Program (NTP) database ( M.I. Luster et al (1992) Fundam. Appl. Toxicol 18:200-210 ).
  • NTP National Toxicology Program
  • a TDAR is dependent on functions of the following cellular compartments: (1) antigen-presenting cells, such as macrophages or dendritic cells; (2) T-helper cells, which are critical players in the genesis of the response, as well as in isotype switching; and (3) B-cells, which arc the ultimate effector cells and are responsible for antibody production.
  • antigen-presenting cells such as macrophages or dendritic cells
  • T-helper cells which are critical players in the genesis of the response, as well as in isotype switching
  • B-cells which arc the ultimate effector cells and are responsible for antibody production.
  • Chemically-induced changes in any one compartment can cause significant changes in the overall TDAR ( M.P. Holsapple In: O.R. Burleson, J.H. Dean and A.E. Munson, Editors, Modem Methods in Immunotoxicology, Volume 1, Wiley-Liss Publishers, New York, NY (1995), pp. 71-108 ).
  • this assay is performed either as an ELISA for measurement of soluble antibody ( R.J. Smialowizc et al (2001) Toxicol. Sci. 61:164-175 ) or as a plaque (or antibody) forming cell assay ( L. Guo et al (2002) Toxicol. Appl. Pharmacol. 181:219-227 ) to detect plasma cells secreting antigen specific antibodies.
  • the antigen of choice is either whole cells (e.g. sheep erythrocytes) or soluble protein antigens ( T. Miller et al (1998) Toxicol. Sci. 42:129-135 ).
  • a compound of Formula 1 may be administered by any route appropriate to the disease or condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal.
  • the compounds may be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the compound of Formula 1 is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient.
  • the compound of Formula I is administered parenterally, it may be formulated with a phannaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
  • a dose to treat human patients may range from about 10 mg to about 1000 mg of a compound of Formula I.
  • a typical dose may be about 100 mg to about 300 mg of a compound of Formula I.
  • a dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • QD once a day
  • BID twice per day
  • toxicity factors may influence the dosage and administration regimen.
  • the pill, capsule, or tablet When administered orally, may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • Another embodiment includes a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the pharmaceutical composition also includes an additional therapeutic agent selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
  • an additional therapeutic agent selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
  • a compound of Formula I is present in a pharmaceutical formulation in an amount to detectably inhibit Janus kinase activity and a phamtaceutically acceptable carrier, adjuvant or vehicle.
  • a compound of Formula I is present in a pharmaceutical formulation in an amount to detectably inhibit a Janus kinase activity and is at least 15 fold, alternatively 10 fold, or 5 fold or more selective in inhibiting one Janus kinase activity over inhibiting one or more of the other JAK1, JAK2, JAK3 and/or Tyk-2 activity.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients arc well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent
  • a suitable solvent in the presence of one or more of the excipients described above.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • formulations of a compound of Formula I may be prepared for various routes and types of administration.
  • a compound of Formula I having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers ( Remington's Pharmaceutical Sciences (1980) 16th edition. Osol, A. Ed .), in the form of a lyophilized formulation, milled powder, or an aqueous solution.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH. and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • the compound of Formula I for use in a pharmaceutical composition is substantially sterile.
  • the compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
  • compositions of the invention will be formulated, dosed, and administered in a fashion, i.e. amounts, concentrations, schedules, course, vehicles, and route of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "therapeutically effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder. Such amount is preferably below the amount that is toxic to the host.
  • the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0.0 1-100 mg/kg, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • Acceptable diluents, carriers, excipients, and stabilizers arc nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspara
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particlcs and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particlcs and nanocapsules
  • Such techniques arc disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980 ).
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a confound of Formula I, which matrices arc in the form of shaped articles e.g. films, or microcapsules.
  • sustained-relcuic matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glvcolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • polyesters for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)
  • polylactides copolymers of L-glutamic acid and gamma-ethyl-L-glutamate
  • non-degradable ethylene-vinyl acetate non-degradable
  • the formulations to be used for in vivo administration must be sterile, which is readily accomplished by filtration through sterile filtration membranes.
  • the formulations include those suitable for the administration routes detailed herein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally arc found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA ). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations arc prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of a compound of Formula I suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of the compound of Formula I.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g. gelatin capsules, syrups or elixirs may be prepared for oral use.
  • Formulations of a compound of Formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets arc acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as starch, ge
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredients) in an amount of for example, 0.075 to 20% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analog.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emugent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Twcen® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmollose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkyl oxide (e.g.
  • ethylene oxide, propylene oxide) with a fatty acid e.g., polyoxyethylene stearate
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., heptadecaethyleneoxycetanol
  • a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride e.g., polyoxyethylene sorbitan monooleate.
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • the pharmaceutical composition of a compound of Formula I may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles, and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as olcic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth: pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HIV infections as described below.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as arc known in the art to be appropriate.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example scaled ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • the compounds of Formula I may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as an immunologic disorder (e.g. psoriasis or inflammation) or a hyperproliferative disorder (e.g., cancer).
  • a compound of Formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer).
  • the second therapeutic agent may be a NSAID or other anti-inflammatory agent.
  • the second therapeutic agent may be a chemotherapeutic agent.
  • the second therapeutic agent of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I such that they do not adversely affect each other.
  • Such compounds are suitably present in combination in amounts that are effective for the purpose intended.
  • a composition of this invention comprises a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent such as an NSAID.
  • Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I, and further comprising, administering a second therapeutic agent.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • the combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.
  • the combination therapy may provide "synergy” and prove “synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation: (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceuticalty acceptable salt or prodrug thereof may be combined with other therapeutic, hormonal or antibody agents such as those described herein, as well as combined with surgical therapy and radiotherapy.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method, or immunological disorder method.
  • the amounts of the compound(s) of Formula I and the other pharmaceutically active immunologic or chemotherapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Another embodiment includes in vivo metabolic products of an administered compound of Formula I. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • Metabolite products typically are identified by preparing a radiolabelled (e.g. 14 C or 3 H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g. greater than about 0.5 mg/kg
  • Another embodiment includes a method of manufacturing a compound of Formula I.
  • the method includes reacting a compound of formula (i): wherein R 1 is defined in Formula I, and X is a leaving group, for example, halogen, -OH, -O(C 1 -C 12 alkyl); with a compound of formulae (iia-c): wherein R 5 is defined in Formula I, and R 10 is hydrogen or R 4 , and R 4 is defined in Formula I; under conditions sufficient to form a compound of Formula I.
  • said conditions include basic conditions, for example, carrying out the reaction in the presence of a base, such as an amine base, for example pyridine or an alikylated amine, such as dialkyl or trialkyl amine (e.g. trimethylamine, triethylamine, diisoproplyamine or diethylamine).
  • a base such as an amine base, for example pyridine or an alikylated amine, such as dialkyl or trialkyl amine (e.g. trimethylamine, triethylamine, diisoproplyamine or diethylamine).
  • said conditions include coupling conditions, for example, carrying out the reaction in the presence of PyAOP, DMAP and an alkylated amine, for example, diisopropylamine.
  • kits for treating a disease or disorder responsive to the inhibition of a Janus kinase includes:
  • the kit further includes:
  • the instructions include instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need therof.
  • the first and second compositions are contained in separate containers.
  • the first and second compositions arc contained in the same container.
  • Containers for use include, for example, bottles, vials, syringes, blister pack, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container includes a compound of Formula I or formulation thereof which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container includes a composition comprising at least one compound of Formula I.
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.
  • the label or package inserts indicates that the composition comprising the compound of Formula I can be used to treat a disorder.
  • the label or package insert may indicate that the patient to be treated is one having a disorder characterized by overactive or irregular kinase acitivity.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • the article of manufacture may comprise (a) a first container with a compound of Formula I contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a chemotherapeutic agent.
  • the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compounds can be used to treat patients at risk of stroke, thrombus or thrombosis disorder.
  • the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • Compounds of Formula I may be assayed for the ability to modulate the activity of Janus protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases in vitro and in vivo.
  • In vitro assays include biochemical and cell-based assays that determine inhibition of the kinase activity.
  • Alternate in vitro assays quantify the ability of the compound of Formula I to bind to kinases and may be measured either by radiolabclling the compound of Formula I prior to binding, isolating the compound of Formula I/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where a compound of Formula I is incubated with known radiolabeled ligands.
  • the compounds of Formula I can be used to control, modulate or inhibit tyrosine kinase activity, for example Janus protein kinase activity, additional serine/threonine kinases, and/or dual specificity kinases.
  • tyrosine kinase activity for example Janus protein kinase activity, additional serine/threonine kinases, and/or dual specificity kinases.
  • the activity of the isolated JAK1, JAK2 or TYK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, MA).
  • Examples 1-508 compounds were diluted serially in DMSO and added to 50 uL kinase reactions containing 1.5 nM JAK1, 0.2 nM purified JAK2 or 1 nM purified TYK2 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 uM peptide substrate, 25 uM ATP, 10 mM MgCl2, 4 mM DTT at a final DMSO concentration of 2%.
  • the activity of the isolated JAK3 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, MA).
  • Ki inhibition constants
  • the proportion of phosphorylated product was determined as a fraction of total peptide substrate using the Caliper LabChip 3000 according to the manufacturer's specifications. Ki values were then determined using the Morrison tight binding model. Morrison. J.F., Biochim. Biophys. Acta. 185:269-296 (1969 ); William, J.W. and Morrison, J.F., Meth. Enzymol., 63:437-467 (1979 ).
  • Examples 1-508 were determined in cell-based assays that arc designed to measure Janus kinase dependent signaling.
  • Compounds were serially diluted in DMSO and incubated with Set-2 cells (German Collection of Microorganisms and Cell Cultures (DSMZ); Braunschweig, Germany), which express the JAK2V617F mutant protein, in 96-well microtiter plates for 1 hr at 37°C in RPMI medium at a final cell density of 10 5 cells per well and a final DMSO concentration of 0.57%.
  • Set-2 cells German Collection of Microorganisms and Cell Cultures (DSMZ); Braunschweig, Germany
  • NK92 cells American Type Culture Collection (ATCC); Manassas, VA) in 96-well microliter plates in RPMI medium at a final cell density of 10 5 cells per well and a final DMSO concentration of 0.57%.
  • IL-2 or IL-12 Human recombinant IL-2 or IL-12 (R&D systems; Minneapolis, MN) was then added at a final concentration of 10ng/mL or 30ng/mL, respectively, to the microtiter plates containing the NK92 cells and compound and the plates were incubated for 1 hr at 37°C.
  • Compound-mediated effects on STATS (IL-2-mediated) or STAT4 (IL-12-mediated) phosphorylation were then measured in the lysates of incubated cells using the Meso Scale Discovery (MSD) technology (Gaithersburg, Maryland) according to the manufacturer's protocol and EC 50 ) values were determined.
  • MSD Meso Scale Discovery
  • Method A Experiments performed on a Waters Micromass ZQ quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with diode array detector. This system uses a Higgins Clipeus 5micron C18 100 x 3.0mm column and a 1 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 5 minutes.
  • Method B Experiments performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with diode array detector and 100 position autosampler using a Phenomenex Luna C18(2) 30 x 4.6mm column and a 2 ml / minute flow rate.
  • the solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes.
  • HPLC Preparative High Pressure Liquid Chromatography
  • Chiral Supercritical Fluid Chromatography was used to separate some racemic compounds into their component enantiomers.
  • the system used was a Berger Pronto SFC equipped with an automated UV-triggered fraction collector.
  • Chiral Technologies AD, OD, OJ, or AS (21.2 x 250 mm) are examples of the columns used. Run lengths varied from 5-10 minutes, and an isocratic mobile phase consisting of 5-50% MeOH:carbon dioxide was used.
  • Microwave experiments were carried out using a Biotage Initiator 60TM which uses a single-mode resonator and dynamic field tuning. Temperature from 40-250°C can be achieved, and pressures of up to 30 bar can be reached.
  • the reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated to yield 232.3 mg (70%) of the crude product.
  • the crude product was purified by reverse phase HPLC and lyophilized to give N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
  • di-tert-butyl iminodicarboxylate (2.566 g, 11.81 mmol, 1.10 cq) was combined with sodium hydride (60% on mineral oil, 0.586 g, 14.6 mmol, 1.37 eq) and 30 mL N,N-dimethylformamide.
  • the reaction mixture was stirred at room temperature for 1.5 hours, and then 2-bromo-1-(2,5-dimethylphenyl)ethanone (2.432 g, 10.71 mmol, 1 eq) was added.
  • the reaction was stirred at room temperature for an additional 1.5 hours, and then partitioned between ethyl acetate and water.
  • N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.255 g, 0.767 mmol, 1 eq) in 10 mL N,N-dimethylformamide is added iodomethane (60.0 ⁇ L, 0.964 mmol, 1.26 eq) and cesium carbonate (0.562 g, 1.72 mmol, 2.25 eq).
  • iodomethane 60.0 ⁇ L, 0.964 mmol, 1.26 eq
  • cesium carbonate 0.562 g, 1.72 mmol, 2.25 eq
  • reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, filtered through a silica gel plug, and concentrated.
  • the crude product was purified by reverse phase HPLC and lyophilized to give 50.0 mg (30%) of N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
  • N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (82.2 mg, 0.247 mmol. 1 eq), 2.5-dichlorophenylboronic acid (122.1 mg, 0.6399 mmol, 2.59 eq), and bis(triphenylphosphine)palladium(II) chloride (15.4 mg, 0.0219 mmol. 0.09 eq) were combined in a microwave vial.
  • sodium carbonate 1.0 mL of a 1.0 M aqueous solution, 1.0 mmol, 4.0 eq
  • 3.0 mL acetonitrile 3.0 mL acetonitrile.
  • the vial was sealed and subjected to microwave irradiation (120°C, 30 W) for 30 minutes.
  • the reaction was partitioned between ethyl acetate and water, and the organic layer dried over magnesium sulfate and concentrated.
  • the crude product was purified by reverse phase HPLC and lyophilized to give 45.3 mg (46%) of N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
  • N,N-diisopropylethylamine (0.20 mL, 1.1 mmol, 2.3 eq)
  • 4-dimethylaminopyridine (24.1 mg, 0.197 mmol, 0.40 cq) in 5.0 mL N,N-dimethylformamide was stirred at 50 °C for 3 hours.
  • the reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated.
  • N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (68.9 mg, 0.203 mmol, 1 eq) was dissolved in 4 mL N,N-dimethylformamide. To this solution was added cesium carbonate (148 mg, 0.454 mmol, 2.23 eq) and isopropyl iodide (23.0 ⁇ L, 0.230 mmol, 1.13 eq). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated.
  • N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (58.9 mg, 0.174 mmol, 1 eq) was dissolved in 5 mL N,N-dimethylformamide. To this solution was added isobutylene oxide (0.5 mL, 6 mmol, 30 eq) and cesium carbonate (56.4 mg, 0.173 mmol, 1.0 eq). The reaction mixture was sttirred at 50 °C for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated.
  • N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-arboxamide 101 mg, 0.313 mmol, 1 eq
  • 2-trifluoromethylphenyl boronic acid (126.6 mg, 0.6666 mmol. 2.13 eq)
  • bis(triphenylphosphine)palladium(II) chloride 26.8 mg, 0,0382 mmol, 0.12 eq
  • sodium carbonate 1.0 mL of a 2.0 M aqueous solution, 2 mmol, 6 eq
  • 3 acetonitrile 3 acetonitrile.
  • reaction mixture was subjected to microwave irradiation at 130 °C for 30 minutes.
  • the reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated.
  • the crude product was purified by reverse phase HPLC and lyophilized to give 4.7 mg (4%) of N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[1-5-a]pyrimidine-3-carboxamide.
  • reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, filtered through a pad of silica gel, and concentrated to give 0.212 g (84%) of N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification.
  • N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (2.0 g, 5.4 mmol), t-butyl-bromoacetate (0.88 mL, 6.0 mmol), and cesium carbonate (2.1 g, 6.5 mmol) were combined and stirred at 30 °C overnight. The mixture was warmed to 65 °C at which time additional carbonate and t-butylbromoacetate was added and stirred 8 hrs. The mixture was cooled to ambient temperature and stirred overnight, then partitioned EtOAc/water.
  • reaction mixture was stirred at room temperature for one hour and then heated at 50°C for 2.5 hours. 4-Nitrobenzoic acid (51 mg), triphenylphosphine (86 mg), and diethylazodicarboxylate (53 ⁇ L) were then added and the reaction mixture heated 50°C overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and evaporated in vacuo.
  • the crude material from the previous step was dissolved in 3 mL tetrahydrofuran with 5.0 M sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ethyl acetate and washed twice with 2M aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate and evaporated in vacuo.
  • the reaction mixture was kept at -60°C for 4 hours, and then 1.0 M lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (0.6 mL, 0.6 mmol) was added. The reaction mixture was kept at -25°C for 8 hours. 1.0 M lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (0.9 mL, 0.9 mmol) was added and the reaction mixture was kept at -25°C for an additional 6 hours until reduction of the ketone is judged complete by LCMS. The reaction mixture was then cooled at -40°C and quenched with 3 mL saturated aqueous ammonium chloride.
  • reaction mixture was kept at -78°C for an additional hour, and then quenched with saturated aqueous ammonium chloride and warmed to room temperature.
  • the reaction mixture was partitioned between ethyl acetate and water, and the organic layer dried over magnesium sulfate and evaporated in vacuo to yield 0.4592 g (98%) of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, which was carried forward without further purification.
  • 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5192 g, 6.2432 mmol) was dissolved in 20 mL THF and cooled at -78°C. To this solution was slowly added 1.0M lithium hexamethyldisilazide in tetrahydrofuran (7.5 mL. 7.5 mmol). After stirring for 40 minutes at -78°C, a solution of iodine (1.7602 g, 6.9351 mmol) in 8 mL THF was slowly added.
  • the reaction mixture was kept at -78°C for an additional 1.5 hours, and then quenched with saturated aqueous ammonium chloride and warmed to room temperature.
  • the reaction mixture was partitioned between ethyl acetate and half-saturated aqueous Na 2 S 2 O 3 .
  • the organic layer was dried with magnesium sulfate, filtered, and evaporated in vacuo.
  • the crude product was purified via flash chromatography on silica gel (0 to 15% ethyl acetate in heptanes) to yield 2.2349 g (97%) of 5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.
  • reaction mixture was diluted in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo.
  • the crude product was purified via flash chromatography on silica gel (0 to 50% ethyl acetate in heptanes) to yield 212.3 mg (52%) of tert-butyl 5-(5-chloro-2-methoxypyridin-3-yl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate.
  • Acetonitrile 200 mL was added to potassium 3-ethoxy-3-oxopropanoate (31.1 g, 182.7 mmol), in a 1000 mL 3-necked flask under N 2 with stirring.
  • the reaction mixture was cooled to 0 °C, then triethylamine (38.8 mL, 278.4 mmol) was added, followed by MgCl 2 (20.71 g, 217.5 mmol).
  • the reaction mixture was warmed to room temperature and stirred for an additional 2.5 h.
  • N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.15 g, 0.42 mmol) was dissolved in 10 mL of DMF, then 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (82 mg, 0.63 mmol) and Cs 2 CO 3 (0.41 g, 1.26 mmol) were added.
  • N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.21 g. 0.58 mmol) was dissolved in 10 mL of DMF.
  • 5-(chloromethyl)-1-methyl-1H-1,2.4-triazole hydrochloride (about 0.1 g, 0.88 mmol) and Cs 2 CO 3 (0.57 g, 1.75 mmol) were added and the mixture was stirred at room temperature overnight.
  • N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 120 mg, 0.334 mmol
  • 3-(chloromethyl)-4-methyl-4H-1,2,4-triazole 65 mg, 0.5 mmol
  • Cs 2 CO 3 325 mg, 1 mmol
  • Trifluoroacetic acid (10 mL) was added dropwise to a solution of tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-yl)propanoate (0.945 g, 1.90 mmol, 1 equiv) in dichloromethane (10 mL). After 2 h, the reaction mixture was concentrated in vacuo to afford crude product (quantitative) which was used without further purification.
  • LCMS (ESI): M+H 441.1.
  • N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50.0 mg, 0.11 mmol), Pd(PPh 3 ) 4 (6.20 mg, 5.35 ⁇ mol), sodium formate (10.9 mg, 0.16 mmol) and DMF (0.5 mL) were sealed, under nitrogen, in a microwave vial and heated to 130°C for 10 minutes using microwave irradiation. The reaction was cooled, DCM was then added and the organics washed with sodium hydrogen carbonate (sat.aq.), water and brine, dried and evaporated to dryness.
  • sodium hydrogen carbonate sodium hydrogen carbonate
  • N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxamide the title compound was prepared following the synthetic procedures described for N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide to give N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pynin-4-carboxamide as a white solid.
  • N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran4-carboxamide the title compound was prepared following the synthetic procedures described for N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with additional purification by trituration in diethyl ether to give N-(4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
  • Examples 172-508 shown in Table 2 were prepared generally following the above-described Examples. For each compound shown in Table 2, the Example number followed is given in the Method column. TABLE 2 Ex Structure Name Mthd LCMS (ESI) m / z 172 N -(3-(5-chloro-2-methoxyphenyl)-1-((2 S, 3 R )-2,3-dihydroxybutyl)-1 H- pyrazol-4-yl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide 132 457.1 173 N-(3-(5-chloro-2-methoxyphenyl)-1-((2R,3R)-2,3-dihydroxybutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 132 457.1 174 N-(3-(5-chloro-2-methoxyphenyl)-1 -((2S,3S)-2,3-
  • the compounds of Examples 1-508 were tested in the above assays (Examples A-C) and found to have K i values of less than about 1 ⁇ M for inhibiting one or both of JAK1 and JAK2 kinases.
  • the compounds of Examples 1-132 were tested in the above assays (Examples A-C) and found to have K i values of less than about I ⁇ M for inhibiting JAK2 kinase.
  • the compounds of Examples 132-508 were tested in the above assays (Examples A-C) and found to have K i values of less than about 1 ⁇ M for inhibiting JAK1 kinase.
  • Table 3 shows enzymatic activity data (K i , ⁇ M) for certain compounds of the present invention run in the above assays (Examples A-C).
  • Table 3 Example JAK1 JAK2 JAK3 TYK2 i 63 0.153 0.023 0.200 0.140 6 0.0462 0.0049 0.152 0.0996 194 0.775 0.110 4.10 0.980 44 0.131 0.018 0.140 0.480 217 0.0021 0.0005 0.0055 0.0023 379 0.0859 0.0263 0.2400 0.4100 158 0.0048 0.0015 0.0530 0.0066 155 0.0042 0.0026 0.2100 0.0650 364 0.0023 0.0062 0.7100 0.0470 283 0.0007 0.0031 0.2700 0.0091 359 0.0010 0.0042 0.6900 0.0460 432 0.0015 0.0057 0.5700 0.0310 0 300 0.0005 0.0025 0.1700 0.0100 170 0.0007 0.0004 0.0130 0.0021 499 0.0016 0.00

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